(P 181) THE DEVELOPMENT OF A NOVEL PDGFRA RESISTANCE MUTATION IN A RECURRENT KIT-MUTANT GASTROINTESTINAL STROMAL TUMOR (GIST)

Objective: GISTs are sarcomas of the gastrointestinal tract that classically arise through mutations in KIT or PDGFRA tyrosine kinases. GISTs can exhibit both temporal and spatial mutational tumor heterogeneity, however, KIT and PDGFRA mutations are traditionally considered mutually exclusive. To date, only one other case of concurrent mutations exists in the literature.

Methods: This patient with histologically confirmed GIST was enrolled on NCT04557969 and underwent complete cytoreductive surgery for metastatic GIST. A tissue section of the primary tumor was sent for next-generation sequencing (NGS) via the National Cancer Institute Comprehensive Oncologic Molecular Pathology and Sequencing Service (NCI-COMPASS) that utilized the TruSight Oncology 500 Gene Panel for detection of somatic mutations. NGS was repeated upon tumor recurrence. A detailed chart review, including medical history, operative reports, pathology reports, and NGS was performed.

Results: This patient is a 51-year-old male who presented with 3 large intra-abdominal masses and was discovered to have a KIT exon 11 GIST on biopsy. He was initiated on imatinib with significant response over one year of therapy. He then underwent exploratory laparotomy with resection of jejunal primary and multiple peritoneal metastases in November, 2023. NGS of the jejunal primary confirmed previously identified KIT exon 11 (p.Val560Asp) mutation. After 1 year of surveillance imaging on adjuvant imatinib, he was found to have an isolated lesion posterior to the left lower rectus. He underwent resection of the mass in March, 2025. NGS of the recurrence demonstrated the previously known KIT exon 11 (p.Val560Asp) mutation, a novel PDGFRA D842Y (p. Asp842Tyr) mutation that is considered imatinib-resistant, and a new pathologic structural copy number variation loss of CDKN2A on chr9:21968226.

Conclusion: This case demonstrates a rare example of a PDGFRA mutation present in a tumor recurrence that arose as a resistance mutation to a baseline KIT mutation. This highlights the temporal heterogeneity of GIST and underscores the importance of repeat NGS to evaluate GIST recurrences and inform subsequent medical therapy.